1. Field of the Invention
The present invention relates to a composition, particularly a pharmaceutical composition, for inhibiting production or secretion of an amyloid .beta. protein. The composition is effective in treating degenerative brain disorders such as senile dementia, Alzheimer's disease, Down's syndrome, etc., amyloid angiopathy, brain disorders caused by amyloid .beta. protein in cerebrovascular diseases, etc.
2. Description of Related Art
Alzheimer's disease is a neurodegenerative disease characterized by senile plaque and neurofibrillar tangles as well as degeneration and loss of neurons. The senile plaques, which are most characteristic of the disease, are deposits composed of amyloid .beta. protein (hereinafter sometimes abbreviated as A.beta.) derived from .beta.-amyloid precursor protein (hereinafter sometimes abbreviated as .beta.APP) as a major component (Biochem. Biophys. Res. Commun., 122, 1131 (1984)), apolipoprotein E (Brain Res., 541, 163 (1991)) and heparan sulfate proteoglycan (Am. J. Pathol., 133, 456 (1988)), etc.
A.beta. of 40 or 42 amino acids exhibits toxicity to neurons (Science, 250, 279 (1990)), and induces neurofibrillar changes (Proc. Natl. Acad. Sci., 90, 7789 (1993)). In patients with familial Alzheimer's disease, mutations on the .beta.APP gene are observed (Lancet, 337, 978 (1991); Nature, 349, 704 (1991); Science, 254, 97 (1991); Nature, 354, 844 (1991)). Cells containing such mutated gene produce and secrete an increased amount of A.beta. (Nature, 360, 672 (1992); Science, 259, 514 (1993); Science, 264, 1336 (1994)).
Patients with Down's syndrome showing cerebral changes pathologically similar to those of Alzheimer's disease (Proc. Natl. Acad. Sci., 82, 4245 (1985)) have trisomy 21 (i.e., three chromosome 21s containing the .beta.APP gene) and promoted expression of the .beta.APP gene and .beta.APP protein in the brain (Science, 235, 880 (1987); N. Eng. J. Med., 320, 1446 (1989)).
Based on these findings, the participation of the abnormal production or secretion of A.beta. in the onset of Alzheimer's disease is considered to be highly important.
It is believed that .beta.APP is metabolized with proteases called .alpha.- and .beta.-secretases through two pathways (Science, 248, 492 (1990); Science, 248, 1122 (1990); Science, 255, 726 (1992); Science, 255, 728 (1992); Nature, 357, 500 (1992)). When .beta.APP is metabolized with a-secretase, .beta.APP is cleaved at position 16 of A.beta., A.beta. is not produced, and the N-terminal fragment of .beta.APP is released out of the cells as secreted .beta.APP, which acts as a neurotrophic factor (Neuron, 10, 243-254 (1993)). On the other hand, when .beta.APP is cleaved with .beta.-secretase, a C-terminal fragment of .beta.APP containing A.beta.is produced. However, it is unclear where the C-terminal fragment or A.beta. is produced in the cells and how A.beta. is secreted out of the cells. In addition, although candidate enzymes for .alpha.- and .beta.-secretases have been reported (J. Biol. Chem., 268, 16699 (1993); Biochemistry, 33, 192 (1994)), they have not identified.
It has been reported that some compounds, phorbol esters (Proc. Natl. Acad. Sci., 89, 3055 (1992)) and M1 muscarinic receptor agonist, carbacol (Science, 258, 302 (1992)) increase the secreted .beta.APP and inhibit A.beta. production or secretion in in vitro various cells. However, these compounds are unsatisfactory in terms of efficacy, safety, etc.